PROJECT SUMMARY/ABSTRACT This K08 proposal will further Carl Koschmann, MD?s training towards his long-term career goal of improving our understanding and treatment of pediatric brain tumors by investigation of the ability to target recurrent mutations in pediatric glioblastoma (GBM) through a precision medicine approach. Dr. Koschmann is a Pediatric Neuro-Oncology physician scientist at the University of Michigan who has already established a presence in his field. This proposal builds on Dr. Koschmann?s previously acquired expertise in pre-clinical animal models of glioma and cancer pharmacology with new training in DNA damage repair pathway analysis and bioinformatics. By carrying out the experiments in this proposal, Dr. Koschmann will obtain these critical new skillsets while producing data that will advance our understanding of the role of ATRX mutation/loss in pediatric GBM. This research will be conducted under the guidance of primary mentor Maria Castro, PhD and an advisory board of accomplished physician scientists with extensive mentoring success. The career development outlined in this proposal includes educational coursework, integration of Dr. Koschmann into a scientific community, and progressive scientific independence over a five-year period. Brain tumors are the leading cause of cancer-related deaths in children under the age of 20, and glioblastoma represents the brain tumor with the poorest prognosis in children and adults. Treatments for pediatric GBM are ineffective and based on regimens designed for adult GBM, which harbor distinct biology and somatic mutations. Recent tumor sequencing has revealed that the histone chaperone ATRX is mutated in 30% of pediatric GBMs and at least 15 other human cancers. Previous work by Dr. Koschmann showed that loss of ATRX results in impaired non-homologous end joining (NHEJ) and increased tumor somatic mutations. However, no studies have explored the ability to therapeutically target these novel findings. In two Specific Aims, this proposal will test the hypothesis that: (1) loss of NHEJ in ATRX-deficient GBM will result in increased sensitivity to agents that target homologous recombination (HR); and (2) mutational burden in ATRX-deficient GBM will generate HLA- recognized glioma neo-antigens amenable to future immunologic checkpoint inhibition. Dr. Koschmann will be ideally positioned to explore these questions through the use of: (1) a novel mouse model of ATRX-deficient GBM, (2) state-of-the-art cancer genomic/bioinformatic techniques, and (3) novel DNA-damaging therapies. This work will build to multiple future R01 proposals, including to: (1) to determine if immunologic checkpoint blockade therapy is effective in ATRX-deficient GBM, and (2) to explore the potential epigenetic mechanisms by which ATRX loss leads to a defect in NHEJ. In summary, this proposal will create highly needed translational data that will improve our understanding and treatments of pediatric GBM. Additionally, this work will provide Dr. Koschmann with the skills needed to create an independent research program that implements a precision medicine approach in the development of therapies for pediatric/young adult GBM.